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The ability to precisely edit genomes with CRISPR/Cas9 and other related editing systems has become integral to the identification of new drug targets and the creation of engineered cell and animal models of disease. The impact of CRISPR in drug discovery is discussed at length throughout this book and is briefly introduced here. The field of Functional Genomics has advanced with the generation of whole genome‐wide CRISPR libraries and other reagents that enable the parallel deletion, upregulation, or downregulation of every gene in the genome to ask the question “what is the effect of modulating this gene on the biology of interest?” (Doench 2018). These libraries can be prepared in micro‐titer plate format with each well of the plate containing a cocktail of guide RNAs designed to delete a single gene. When screened against cellular models of disease, it becomes possible to identify specific genes which when modulated affect the biology under study. In addition to use for the identification of new drug targets, Functional Genomic screens are being applied widely to address questions such as the identification of genes that when modulated enable an increase in recombinant protein expression or an increase in the productive uptake of lipid nanoparticles. A further application of Functional Genomic screens in Oncology is the screening of whole genome‐wide CRISPR libraries against multiple cancer cell lines in the presence of known cancer medicines to identify genes that mediate resistance or sensitization to that medicine. Many hundred such screens have been performed at Institutes such as the Broad Institute and the Wellcome Trust Sanger Centre to create public domain databases that describe so‐called sensitivity maps of cancer types to drug action (Behan et al. 2019; Cui et al. 2021). Such studies are enabling the targeting of new medicines to specific tumor types, the identification of likely resistance mechanisms to new medicines, and drug combination opportunities in the clinic.

CRISPR is widely applied to create cellular and animal models of disease, both for the identification of new drug targets and for understanding the efficacy of new drug candidates within a discovery program (Lundin et al. 2020). CRISPR is used to create specific mutations in genes to understand the effect of that mutation on gene function and to introduce molecular tags into genes to track gene expression. The latter approach has been widely adapted to characterize the efficacy of Proteolysis Targeting Chimeras (PROTACs) drugs. PROTACs are a recently discovered class of small‐molecule drugs that rather than inhibiting the function of a drug target, act to degrade the target protein. To understand the efficacy of PROTAC drugs in cellular models of disease, the drug target is typically tagged with a short protein sequence that enables the creation of assays that allow PROTAC‐mediated degradation of the target to be followed in real time in an immortalized cell line or animal model of disease. CRISPR has revolutionized the ability to generate transgenic animal models of disease, both reducing the timelines and number of animals required for the creation of an animal model through the ability to highly efficiently edit the genome of the single cell embryo, while again enabling the creation of complex models of disease not previously possible.

CRISPR is being widely applied in the field of CAR‐T cell therapy both to enable precise insertion of the CAR, but also to identify and delete other T‐cell genes to enable improved efficacy of the cell product (Liu et al. 2017). There is also huge interest in the potential of CRISPR as a medicine in its own right to correct gene mutations in rare and perhaps common diseases and a number of biotechnology companies have been established to bring CRISPR medicines to the clinic, including Editas, CRISPR Therapeutics, Beam Therapeutics, Verve Therapeutics and Intellia. The first clinical studies of medicines to treat β‐thalassemia and Sickle Cell Disease started in 2019 with highly promising results in the first patients, with the first in‐vivo gene editing clinical trials in diseases such as Transthyretin amylodosis in which CRISPR is being used to delete genes in the patient liver, due to start in 2022. Many further projects are in discovery to develop treatments for a range of diseases including α1‐antitrypsin deficiency and Cystic Fibrosis.

Last and perhaps one of the most exciting applications of CRISPR in drug discovery is the potential to create highly sensitive, inexpensive, point‐of‐care diagnostics for the early detection of disease (Chen et al. 2018; Gootenberg et al. 2018; Myhrvold et al. 2018). It is widely accepted, particularly in Oncology, that the probability of patient survival from the disease increases with early disease detection. The creation of diagnostics that detect cancer in stage 1 rather than when symptomatic in stage 3 or 4 will transform our ability to treat and perhaps cure this disease. Two methods have been published, described as SHERLOCK and DETECTR, that offer the potential to create such sensitive DNA diagnostics. While in early development, the potential of these innovations is huge and are being applied more broadly, including for the creation of a diagnostic test for the SARS‐CoV2 virus.